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Racemic Beta-Blockers - Fixed Combinations of Different Drugs Journal of Clinical and Basic Cardiology An Independent International Scientific Journal Journal of Clinical and Basic Cardiology 1998; 1 (1), 15-19 Racemic beta-blockers - fixed combinations of different drugs Stoschitzky K, Lindner W, Zernig G Homepage: www.kup.at/jcbc Online Data Base Search for Authors and Keywords Indexed in Chemical Abstracts EMBASE/Excerpta Medica Krause & Pachernegg GmbH · VERLAG für MEDIZIN und WIRTSCHAFT · A-3003 Gablitz/Austria CURRENT OPINION J Clin Bas Cardiol 1998; 1: 14 Racemic beta-blockers Racemic beta-blockers – fixed combinations of different drugs K. Stoschitzky, G. Zernig1, W. Lindner2 Beta-blockers were introduced in clinical practice in the 1960s as racemic mixtures consisting of d- and l-enantiomers in a fixed 1:1 ratio. Little has changed on this issue although it has been clearly shown in vitro as well as in human studies that only the l-enantiomers exert beta-blockade when clinical doses of the racemic drugs are used, the d-enantiomers not contributing to this effect. In recent years numerous specific as well as non-specific effects of d-enantiomers of beta-blockers have been reported. Therefore, these non beta-blocking d-enantiomers may increase or even cause serious side effects on their own. In addition, pharmacokinetic properties of the l- and d-enantiomers vary widely even when they are given in the fixed 1:1 ratio of a racemic drug, particularly when exercise is performed. In conclusion, the data actually available on this issue demonstrate profound and clinically significant differences between the d- and l-enantiomers of beta-blockers. Therefore, the d- and l-enantiomers of beta-blocking drugs should be recognized and used as individual drugs on their own. We suggest that the so called ‘chiral switch’ be performed, ie, replace the currently used racemic mixtures with the optically pure l-enantiomers since the best available beta-blocking drugs should not be withheld from patients receiving beta-blockers. Such a procedure is further supported by the facts that the l-enantiomers can nowadays be provided easily and at low cost, and that the pure enantiomers give the full effect at half the dose of the currently used racemic mixtures. J Clin Bas Cardiol 1998; 1: 14–8. Key words: Beta-blockers, enantiomers, stereoselectivity, chirality ll beta-blockers that are currently available possess an Nomenclature of stereoisomers A amino-alkanol side chain with an asymmetric carbon atom (Fig. 1), resulting in the existence of a d- and l-enantiomer The (R)- and (S)-nomenclature according to Cahn, Ingold which are mirror images [1] (Fig. 2). Although in vitro studies and Prelog (CIP) priority rules [12] defines the absolute con- showed in the 1960s that the l-enantiomers are orders of figuration of a stereogenic centre, in the present case a tetra- magnitude more potent than the respective d-forms [2], most coordinated carbon atom substituted by four different ligands. beta-blockers are still used as racemates in research as well as On the other hand, the prefixes d- and l- as well as the (+)– in clinical practice as though they were pure drugs. Within and (–)-nomenclature give information according to the rota- this context, it has been argued over a long period of time that tion of polarised light to the right or to the left, and therefore, “the limited experience from studies where these isomers had merely describe these physicochemical properties of the enan- been used separately even suggests that they have no adverse tiomers. All beta-blockers that are currently used in clinical effects at all. Based upon these considerations and in view of practice contain an asymmetric carbon atom. In the aryloxy- the sometimes cumbersome and expensive separation of the propanolamine type compounds the d-enantiomers show the isomers, most beta-receptor blocking agents are now used as (R)-configuration, and the l-enantiomers show the (S)-con- racemates [3]”. Indeed, specific effects of the non beta- figuration. (S)-enantiomers usually are orders of magnitude blocking d-enantiomers of beta-blockers were unknown at more potent in blocking adrenergic beta-adrenoceptors than this time. However, during recent years a number of studies the respective (R)-forms. An exception is sotalol where the have been published reporting highly specific effects of the d- asymmetric carbon atom is located in an ethanolamine type side enantiomers of beta-blockers such as antiarrhythmic class-1 chain. In this case, the priority of the four substituents changes effects [4] and inhibition of the conversion of thyroxin to according to the CIP rules [12] so that (R)-sotalol (equivalent triiodothyronin by d-propranolol [5, 6], or antiarrhythmic to l-sotalol) is much more effective as a beta-blocker than (S)- class-3 effects of d-sotalol [7]. In addition, there are marked sotalol (equivalent to d-sotalol). pharmacokinetic differences between the d- and l-enantiomers In order to offer a homogenous nomenclature for all beta- of most beta-blockers, particularly under exercise [8] and when blocking drugs throughout the article, we predominantly use extensive and poor metabolisers are compared [9, 10]. Never- the d- and l-nomenclature (for the hydrochloride salts of the theless, the potential clinical impact of these findings still beta-blocking substances, when applicable, dissolved in water) remained doubtful. However, the SWORD study [11] showed where the l-enantiomers exert beta-blockade whereas the d- that optically pure d-sotalol increased mortality in patients with enantiomers do not whenever clinical doses of a beta-blocker myocardial infarction by 65 % compared with placebo. Thus, are used. However, it should be stated again, from a the first clinical trial investigating the effects of an optically stereochemical point of view, that only the CIP nomenclature pure d-enantiomer, d-sotalol, emphasised the potential harm is configurationally descriptive according to the spatial that may be caused by a non beta-blocking d-enantiomer of a arrangement of the substituents of an asymmetric centre in a currently used racemic beta-blocker. three-dimensional space. When no prefixes are used at all this The objective of the present review is to highlight the pre- implies that the racemic mixture is used. sent state-of-the-art in chiral aspects of beta-adrenoceptor antagonists. Received April 6th, 1998; accepted April 30th, 1998. From the Div of Cardiology, Dept of Medicine, Karl Franzens University, Graz; 1Div of Neurochemistry, Dept of Psychiatry, Leopold Franzens University, Innsbruck; 2Institute of Analytical Chemistry, University of Vienna; Austria. Correspondence to: Dr Kurt Stoschitzky, Medizinische Universitätsklinik, Abteilung für Kardiologie, Auenbruggerplatz 15, A-8036 Graz, Austria. CURRENT OPINION Racemic beta-blockers J Clin Bas Cardiol 1998; 1: 15 Figure 1: Structural similarity of (S)-propranolol and (S)-propa- fenone. The framed part shows the aminoalkanol chain that is common to all beta-blockers currently used in clinical practice (except sotalol). Hence, the asymmetric carbon atom (marked by an asterisk) is a common feature of all beta-adrenoceptor anta- gonists. Principles of stereoselectivity in beta-adrenoceptor antagonists Figure 2: Structural formula of the (R)- and (S)-enantiomers of propranolol which behave like mirror images. The asymmetric All beta-blockers that are currently used in research as well as carbon atom is marked by an asterisk. in clinical practice are structurally related to the beta-agonists epinephrine and norepinephrine. As a common feature, these nal effects may be used for particular therapeutic indications, catecholamines and all beta-blockers possess an asymmetric or they can merely contribute to and therefore worsen (specific carbon atom. Effects of agonists as well as of antagonists on or non specific) side effects of (racemic) beta-blockers. adrenergic beta-receptors are highly stereoselective with the Other non-specific effects, formerly also termed membrane l-enantiomers being markedly more potent than the respective stabilizing activity (MSA), particularly occur in lipophilic rat- d-forms. Therefore, and in clear contrast to the racemic beta- her than in hydrophilic beta-blockers. They usually only show blockers widely used in therapeutics, the human organism either weak or no stereoselectivity. Thus, side effects of racemic stereoselectively synthesises and uses the active enantiomers, beta-blockers caused by such unspecific effects equally reside ie, l-epinephrine and l-norepinephrine. Hence, it is not sur- in both the d- and l-enantiomers and might therefore be prising that the l-enantiomers of all beta-blockers are orders reduced by approximately 50 % by omitting the non-beta- of magnitude more potent in blocking beta-adrenoceptors than blocking d-enantiomers from the currently used racemic the respective d-forms [13]. Figure 4 shows the markedly dif- drugs. ferent affinities of the d- and l-enantiomers of propranolol, atenolol and propafenone to beta-adrenoceptors in vitro [14– 16], Figure 3 depicts the effects of d-, l- and d,l-atenolol and placebo on heart rate in humans emphasising that half the dose of l-atenolol is equally as effective as racemic d,l-atenolol suggesting that the full beta-blocking efficacy of the racemic drug resides in its l-enantiomer [15]. On the other hand, both d-atenolol and placebo show no effect [15]. However, it should be noted that propafenone, which is mainly used as a class 1c antiarrhythmic agent, also exerts weak beta-blocking effects due to its structural resemblance to beta-adrenoceptor anta- gonists (Fig. 1 and 4) [16]. When beta-blocking effects of the d- and l-enantiomers have been compared, the results were similar both in in vitro and in human studies, revealing that the l-enantiomers are markedly more effective than the respective d-forms. This has been shown for a variety of beta-blockers such as proprano- lol [2, 6, 14], atenolol [15], metoprolol [17], sotalol [7], carvedilol [18, 19], propafenone [16, 20] and others.
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